2,3-Butanediol diester derivatives, process for producing the same, and an antiulcer drug containing the same

ABSTRACT

The specification describes as antiulcer drug containing as an active ingredient a 2,3-butanediol diester derivative represented by the formula (I): ##STR1## where R A  may for example be a saturated or unsaturated alkyl or phenyl styryl group and R B  may for example be a saturated or unsaturated alkyl, phenyl, phenylalkyl, phenylpropenyl or phenoxyalkyl group. These groups may optionally be substituted. Many of 2,3-butanediol diester derivatives embraced by the formula (I) are novel. Also described are a novel process for preparing such novel 2,3-butanediol diester derivatives. The 2,3-butandiol diester derivatives of the formula (I) has an action to depress strongly the growth of peptic ulcer and has a very low toxicity.

BACKGROUND OF THE INVENTION

(1) Field of the Invention

The present invention relates to 2,3-butanediol diester derivatives,process for producing the same, and an antiulcer drug containing thesame.

(2) Description of the Prior Art

Heretofore, it has been known that coixenolide, a constituent of coixseed, has an antitumor effect (Japanese Patent Publication No. 36-13349)and some 2,3-butanediol diesters can be used as a durable perfume/flavoragent or modifier (Japanese Patent Laid-open No. 55-154940).

SUMMARY OF THE INVENTION

The present inventors have carried out a series of researches on thepharmacological actions of 2,3-butanediol diester derivatives(abbreviated as "butanediol diester" hereunder), and as the result ofthese researches, they have discovered that the butanediol diesterrepresented by the formula (I) ##STR2## where R_(A) is a saturated orunsaturated alkyl group which may have a branched chain, or a grouprepresented by ##STR3## (where R₁ is a hydrogen atom, cyano group, orlower alkyl group, and R₂ is a hydrogen atom, halogen atom, lower alkylgroup, lower alkyloxy group, or lower acyloxy group); R_(B) is asaturated or unsaturated alkyl group which may have a branched chain,phenyl group which may be substituted with lower alkyl group, loweralkoxy group or halogen atom, phenyl alkyl group, phenyl propenyl group,phenyloxy alkyl group, or a group represented by ##STR4## (where R₃ is ahydrogen atom, halogen atom, cyano group, lower alkyl group, or phenylgroup, and R₄ is a hydrogen atom, lower alkyl group, or phenyl group,and R₅ is a phenyl group which may be substituted with lower alkylgroup, lower alkoxy group, acyloxy group or halogen atom). has an actionto depress strongly the growth of peptic ulcer and has a very lowtoxicity and that among the compounds represented by the formula (I) thecompound represented by the following formula (II) is a novel compound:##STR5## where R_(A) is as defined above, R_(B) ' is a phenyl groupwhich may be substituted with lower alkyl group, lower alkoxy group orhalogen atom, phenyl alkyl group, phenyl propenyl group, phenyloxy alkylgroup, or a group represented by ##STR6## (where R₃ is a hydrogen atom,halogen atom, cyano group, lower alkyl group, or phenyl group, and R₄ isa hydrogen atom, lower alkyl group, or phenyl group, and R₅ is a phenylgroup which may be substituted with lower alkyl group, lower alkoxygroup, acyloxy group or halogen atom).

Therefore, it is an object of the present invention to provide anantiulcer drug containing a butanediol diester represented by theformula (I).

It is another object of the present invention to provide a novelbutanediol diester represented by the formula (II).

It is a further object of the present invention to provide a process forproducing the butanediol diester represented by the formula (II).

DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

The butanediol diester (I) of this invention is a known compound or anovel compound produced by a process based on known reaction or any oneof the following processes.

Process for production:

(1) According to this process, 2,3-butanediol (III) is converted to a2,3-butanediol monoester derivative (V) by the reaction with acarboxylic acid (IV) or an active derivative thereof, and (V) isconverted to the object compound (I) by the reaction with a carboxylicacid (VI) or an active derivative. ##STR7## where R_(A) and R_(B) are asdefined above.

(2) According to this process, 2,3-butanediol (III) is converted to a2,3-butanediol monoester derivative (VII) by the reaction with acarboxylic acid (VI) or an active derivative thereof, and (VII) isconverted to the object compound (I) by the reaction with a carboxylicacid (IV). ##STR8## where R_(A) and R_(B) are as defined above.

(3) According to this process, 2,3-butanediol (III) is converted to a2,3-butanediol diester derivative (I') by the reaction with a carboxylicacid (IV) or an active derivative thereof in twofold moles. ##STR9##where R_(A) is as defined above.

Examples of the active derivatives of the carboxylic acids (IV) and (VI)used in these processes include acid halogenide, acid anhydride, andmixed acid anhydrides. If these compounds are to be used, the reactionshould preferably be carried out in the presence of a deacidifier suchas pyridine, tertiary amine, alkali carbonate, alkali hydroxide, andhydrogenated alkali.

Typical butanediol diesters produced by the above processes are shown inTable 1, in which compounds No. 1 to 21 are known and compounds No. 22to 81 are novel.

      Compound    Melting  No. R.sub.A R.sub.B n.sub.D.sup.20 point °C.      NMR (δppm: CCl.sub.4)       1 (CH.sub.2).sub.6 CH.sub.3 (CH.sub.2).sub.6      CH.sub.3 1.436  4.7˜5.2(m.2H) 2.3(t.4H) 1.1˜1.9(m.26H)     0.9(t.6H) 2 (CH.sub.2).sub.7 CH.sub.3 (CH.sub.2).sub.7 CH.sub.3 1.439     4.7˜5.1(m.2H) 2.2(t.4H) 1.1˜1.9(m.30H)      0.9(t.6H) 3     (CH.sub.2).sub.8 CH.sub.3 (CH.sub.2).sub.8      CH.sub.3 1.444  4.7˜5.2(m.2H) 2.2(t.4H) 1.1˜1.9(m.34H)     0.9(t.6H) 4 (CH.sub.2).sub.9 CH.sub.3 (CH.sub.2).sub.9 CH.sub.3 1.445     4.6˜5.2(m.2H) 2.2(t.4H) 1.1˜1.9(m.38H)      0.9(t.6H) 5     (CH.sub.2).sub.10 CH.sub.3 (CH.sub.2).sub.10 CH.sub.3  40˜42     4.7˜5.2(m.2H) 2.3(t.4H) 1.1˜1.9(m.42H)      0.9(t.6H) 6     (CH.sub.2).sub.12 CH.sub.3 (CH.sub.2).sub.12 CH.sub.3  51˜53     4.7˜5.2(m.2H) 2.3(t.4H) 1.1˜1.9(m.50H)      0.9(t.6H) 7     (CH.sub.2).sub. 14 CH.sub.3 (CH.sub.2).sub.14 CH.sub.3  55˜57     4.7˜5.2(m.2H) 2.3(t.4H) 1.1˜1.8(m.58H)      0.9(t.6H)  8      ##STR10##      ##STR11##      1.426  4.6˜5.2(m.2H) 2.0˜2.6(m.2H) 1.0˜2.0(m.16H)     0.9(t.6H)      9     ##STR12##      ##STR13##      1.429  4.7˜5.2(m.2H) 2.1˜2.7(m.2H) 1.1(d.6H)0.7˜1.8(m.     20H)      10     ##STR14##      ##STR15##      1.433  4.7˜5.2(m.2H) 2.1˜2.4(m.4H) 1.6˜2.1(m.2H)1.1.ab     out.1.5(m.4H) 1.2(d.6H) 0.95(d.6H) 0.9(t.6H)      11     ##STR16##      ##STR17##      1.432  4.7˜5.2(m.2H) 2.4(t.4H) 1.5(m.6H)1.2(d.6H) 0.9(d.12H)  12      ##STR18##      ##STR19##      1.437  4.6˜5.1(m.2H) 1.8-2.4(m.6H) 0.8-1.5(m.16H) 0.9(s.18H)  13     CH.sub.2 CH.sub.2 CHCH.sub.2 CH.sub.2 CH.sub.2 CHCH.sub.2 1.446     5.4˜6.1(m.2H) 4.6˜5.2(m.3H) 2.3(m.8H)      1.1(d.6H) 14     CHCH(CH.sub.2).sub.6 CH.sub.3 CHCH(CH.sub.2).sub.6 CH.sub.3 1.464     6.5˜7.1(m.2H) 5.7(d.2H) 4.7˜5.2(m.2H)      1.9˜2.5(m.4H     ) 1.0-1.9(m.26H) 0.9(t.6H) 15 (CH.sub.2).sub.7      CHCHCH.sub.2 (CH.sub.2).sub.7 CHCHCH.sub.2 1.471  5.1˜5.5(m.8H)     4.6˜5.1(m.2H) 2.6˜3.0  CHCH(CH.sub.2).sub.4 CH.sub.3     CHCH(CH.sub.2).sub.4      CH.sub.3   (m.4H) 0.8˜2.5(m.56H) 16 (CH.sub.2).sub.6 CH.sub.2     (CH.sub.2).sub.6      CH.sub.2 1.481  5.0˜5.5(m.12H) 4.5˜5.1(m.2H) 2.5˜3.0  (     CHCHCH.sub.2).sub.3 CH.sub.3 (CHCHCH.sub.2).sub.3 CH.sub.3   (m.8H)     0.8˜2.5(m.44H) 17 (CH.sub.2).sub.9 CH.sub.3 (CH.sub.2).sub.4     CH.sub.3 1.440  4.7˜5.1(m.2H) 2.3(t.4H) 1.1˜1.9(m.28H)     0.9(t.6H) 18   " (CH.sub.2).sub.6 CH.sub.3 1.443  4.7˜5.1(m.2H)     2.2(t.4H) 1.1˜2.0(m.30H)      0.9(t.6H) 19   " (CH.sub.2).sub.8     CH.sub.3 1.445  4.7˜5.1(m.2H) 2.2(t.4H) 1.1˜2.0(m.32H)     0.9(t.6H) 20   " CHCHCH.sub.8 1.450  6.5˜7.1(m.1H) 5.75(m.1H)     4.7˜5.1(m.2H) 2.2   trans   (t.2H) 1.9(dd.3H) 1.1˜1.8(m.22H)     0.9(t.3H) 21   " (CH.sub.2).sub.7      CHCH(CH.sub.2).sub.7 1.456  5.0˜5.5(m.2H) 4.6˜5.0(m.2H)     1.1˜2.4   cis-CH.sub.3   (m.52H) 0.9(t.6H)  22 (CH.sub.2).sub.4     CH.sub.3      ##STR20##      1.514  7.6(d.1H) 7.2˜7.6(m.5H) 6.3(d.1H) 4.7˜5.3(m.2H)2.25(t     .2H) 1.0˜1.9(m.12H) 0.9(t.3H)  23 (CH.sub.2).sub.6 CH.sub.3   "     1.509  7.6(d.1H) 7.2˜7.5(m.5H) 6.3(d.1H) 4.7˜5.3(m.2H)     2.25(t.2H) 1.0˜1.9(m.16H) 0.9(t.3H) 24 (CH.sub.2).sub.7 CH.sub.3     " 1.505  7.6(d.1H) 7.2˜7.5(m.5H) 6.3(d.1H) 4.7˜5.3(m.2H)      2.25(t.2H) 1.0˜1.9(m.18H), 0.9(t.3H) 25 (CH.sub.2).sub.8 CH.sub.3       " 1.501  7.7(d.1H) 7.3˜7.7(m.5H), 6.4(d.1H) 4.8˜5.7(m.2H)         2.0˜2.5(t.2H), 1.0˜1.8(m.20H) 0.9(t.3H) 26 (CH.sub.2).sub     .9 CH.sub.3      " 1.503  7.6(d.1H) 7.2˜7.5(m.5H) 6.3(d.1H) 4.7˜5.2(m.2H)       2.2(t.2H) 1.0˜1.8(m.22H) 0.9(t.3H) 27 (CH.sub.2).sub.10 CH.sub.3       " 1.500  7.6(d.1H), 7.1˜7.5(m.5H), 6.3(d.1H) 4.7˜5.2(m.2H)          2.2(t.2H) 1.0˜1.8(m.24H) 0.9(3H) 28 (CH.sub.2).sub.8      CHCH.sub.2      " 1.509  7.6(d.1H) 7.3(m.5H) 6.35(d.1H) 5.4˜6.1(m.1H)     4.7˜5.3(m.4H) 2.2(t.2H) 1.0˜2.1(m.20H) 29 (CH.sub.2).sub.7   C     CHH(CH.sub.2).sub.7 CH.sub.3   " 1.503  7.6(d.1H) 7.1˜7.5(m.5H)     6.8(d.1H) 5.1˜5.4(m.2H)  (cis)    4.8˜5.1(m.2H) 1.0˜2.4     (m.34H) 0.9(t.3H) 30 (CH.sub.2).sub.7 CHCH(CH.sub.2).sub.7 CH.sub.3   "     1.505  7.65(d.1H) 7.2˜7.5(m.5H) 6.35(d.1H) 5.2˜5.5(m.2H)     (trans)    4.9˜5.2(m.2H) 1.1˜2.5(m.34H) 0.9(t.3H)  31     (CH.sub.2).sub.4      CH.sub.3     ##STR21##      1.504  7.55(d.1H) 7.3(d.1H) 7.05(d.1H) 6.3(d.1H) 4.7˜5.2(m.1H)2.3(     s.3H) 2.0˜2.4(t.2H) 1.0˜2.0(m.12H) 0.9(t.3H)      32 (CH.sub.2).sub.9 CH.sub.3   " 1.499  7.5(d.1H) 7.35(d.2H) 7.05(d.2H)     6.25(d.1H) 4.7˜5.3(m.2H)      2.35(s.3H) 2.2(t.2H) 1.1˜1.9(m.     22H) 0.9(t.3H)      33     ##STR22##      "  72˜74 7.5(d.2H) 7.35(d.4H) 7.15(d.4H) 6.35(d.2H)4.7˜5.1(m     .2H) 2.3(s.6H) 1.4(d.6H)  34 (CH.sub.2).sub.4      CH.sub.3     ##STR23##      1.528  7.5(d.1H) 7.4(d.2H) 6.8(d.2H) 6.15(d.1H)4.7˜5.3(m.2H)     3.8(s.2H) 2.2(t.2H)1.0˜1.9(m.12H) 0.9(t.3H)  35 (CH.sub.2).sub.9     CH.sub.3   " 1.519  7.5(d.1H) 7.4(d.2H) 6.8(d.2H) 6.15(d.1H)     4.7˜5.2(m.2H) 3.8(s.3H) 2.2(t.2H)      1.0˜1.9(m.22H)     0.9(t.3H)      36     ##STR24##      "  115˜117 7.6(d.2H) 7.4(d.2H) 7.3(d.2H) 6.3(d.2H)4.9˜5.4(m.     2H) 3.8(s.6H) 1.4(d.6H)  37 (CH.sub.2).sub.4      CH.sub.3     ##STR25##      1.524  7.6(d.1H) 7.4(d.d.4H) 6.35(d.1H) 4.8˜5.4(m.2H)2.3(t.3H)     1.1˜1.9(m.12H) 0.9(t.3H)  38 (CH.sub.2).sub.9 CH.sub.3   " 1.514     7.6(d.1H) 7.4(d.d.4H) 6.35(d.1H) 4.8˜5.4(m.2H)      2.3(t.3H)     1.1˜1.9(m.22H) 0.9(t.3H)      39     ##STR26##      "  133˜136 7.6(d.2H) 7.3(m.8H) 6.3(d.2H) 4.9˜5.4(m.2H)1.3(d.     6H)  40 (CH.sub.2).sub.9      CH.sub.3     ##STR27##      1.520  7.45(d.1H) 6.65(s.2H) 6.2(d.1H)4.8˜5.3(m.2H) 3.78(d.9H)     2.2(t.2H)1.0˜1.9(m.22H) 0.9(t.3H)  41      "     ##STR28##      1.507  7.55(d.1H) 7.5(d.2H) 7.05(d.2H) 6.3(d.1H)4.7˜5.2(m.2H)     2.25(s.3H) 2.2(t.2H)1.1˜2.0(m.22H) 0.9(t.3H)      42     ##STR29##      "  112˜116 7.6(d.2H) 7.45(d.4H) 7.05(d.4H) 6.3(d.2H)5.0˜5.4(     m.2H) 2.3(s.6H) 1.35(d.6H)      43     ##STR30##      ##STR31##       177˜180 8.25(s.2H) 7.8˜8.1(m.4H) 7.3˜7.7(m.6H)5.1.abo     ut.5.5(m.2H) 1.4(d.6H)  44 (CH.sub.2).sub.4 CH.sub.3      " 1.523  8.15(s.1H) 7.7˜8.1(m.2H) 7.2˜7.7(m.3H)     4.7˜5.4(m.2H) 2.25(t.2H) 1.0˜1.9(m.12H) 0.9(t.3H) 45     (CH.sub.2).sub.6 CH.sub.3   " 1.509  8.15(s.1H) 7.7˜7.8(m.2H)     7.3˜7.7(m.3H)      4.8˜5.3(m.2H) 2.25(t.2H) 1.0˜2.0(m.1     6H) 0.9(t.3H) 46 (CH.sub.2).sub.7 CH.sub.3      " 1.516  8.2(s.1H) 7.8˜8.1(m.2H) 7.3˜7.7(m.3H)     4.7˜5.3(m.2H) 2.3(t.2H) 1.0˜1.8(m.18H) 0.9(t.3H) 47 (CH.sub.2     ).sub.8      CH.sub.3     ##STR32##      1.514  8.15(s.1H) 7.7˜8.1(m.2H) 7.2˜7.7(m.3H) 4.7˜5.4(     m.2H) 2.25(t.2H) 1.0˜1.9(m.20H) 0.9(t.3H) 48 (CH.sub.2).sub.9     CH.sub.3   " 1.514  8.13(s.1H) 7.7˜8.1(m.2H) 7.3˜7.7(m.3H)        4.8˜5.3(m.2H) 2.0˜2.5(t.2H) 1.0˜1.9(m.22H)     0.9(t.3H) 49 (CH.sub.2).sub.10 CH.sub.3      " 1.512  8.1(s.1H) 7.8˜8.1(m.2H) 7.3˜7.6(m.3H)     4.8˜5.4(m.2H) 2.3(t.2H) 1.1˜1.7(m.24H) 0.9(t.3H) 50 CHCHCH.su     b.3   "  78˜81 8.1(s.1H) 7.7˜8.1(m.2H) 7.3˜7.6(m.3H)        6.6˜7.1(m.1H) 5.6˜6.0(m.1H) 4.7˜5.3(m.2H)     1.85(d.d.3H) 1.30(d.3H) 1.25(d.3H)      51     ##STR33##      " 1.550  8.1(s.1H) 7.7˜8.1(m.2H) 7.3˜7.6(m.3H)6.5˜7.0(     m.1H) 4.8˜5.4(m.2H) 1.8(s.3H)1.75(d.3H) 1.35(d.3H) 1.3(d.3H)  52     (CH.sub.2).sub.7 CHCH(CH.sub.2).sub.7 CH.sub.3   " 1.509  8.1(s.1H)     7.7˜8.0(m.2H) 7.2˜7.6(m.3H)  (cis)    4.7˜5.4(m.4H)     1.0˜2.4(m.34H) 0.9(t.3H)  53 (CH.sub.2).sub.7 CHCH(CH.sub.2).sub.7     CH.sub.3   "  8.1(s.1H) 7.7˜8.0(m.2H) 7.2˜7.6(m.3H)  (Trans)        4.7˜5.4(m.4H) 1.0˜2.4(m.34H) 0.9(t.3H)      54 (CH.sub.2).sub.4      CH.sub.3     ##STR34##      1.506  7.6(m.1H) 7.3(b.s.5H) 4.8˜5.3(m.2H)2.25(t.2H) 2.1(d.3H)     1.0˜2.0(m.12H)0.9(t.3H)  55 (CH.sub.2).sub.9 CH.sub.3   " 1.501     7.6(m.1H) 7.34(b.s.5H) 4.8˜5.3(m.2H)      2.25(t.2H) 2.1(d.3H)     1.1˜2.0(m.22H)      0.9(t.3H) 56 (CH.sub.2).sub.10 CH.sub.3   "     1.500  7.6(m.1H) 7.3(b.s.5H) 4.8˜5.3(m.2H)      2.25(t.2H)     2.1(d.3H) 1.0˜2.0(m.24H)     0.9(t.3H)      57     ##STR35##        " 1.559  7.6(m.1H) 7.3(b.s.5H) 4.9˜5.4(m.2H)2.1(m.6H) 1.4(d.6H)      58 (CH.sub.2).sub.4      CH.sub.3     ##STR36##      1.480  7.8˜8.2(m.2H) 7.2˜7.7(m.3H) 4.7˜5.3(m.2H)     2.2(t.2H)1.0˜1.9(m.12H) 0.9(t.3H)  59      "     ##STR37##      1.481  7.8(d.2H) 7.1(d.2H) 4.7˜5.3(m.2H) 2.3(s 3H) 2.0˜2.4(t     .2H) 1.1˜2.0(m.12H) 0.9(t.3H)  60      "     ##STR38##      1.492  7.9(d.2H) 6.9(d.2H) 4.8˜5.4(m.2H) 3.8(s.3H) 2.0˜2.4(t     .2H) 1.1˜2.0(m.12H) 0.9(t.3H)  61      "     ##STR39##      1.492  7.7(d.2H) 7.2(d.2H) 4.7˜5.3(m.2H) 2.0˜2.4(t.2H)1.1.ab     out.2.0(m.12H) 0.9(t.3H)  62      "     ##STR40##      1.493  7.2(s.2H) 4.8˜5.4(m.2H) 3.8(d.9H) 2.2(t.2H)1.0˜2.0(m.     12H) 0.9(t.3H)  63      "     ##STR41##      1.498  7.0˜7.5(m.5H) 6.0˜6.6(m.2H) 4.6˜5.2(m.2H)     3.2(d.2H)2.0˜2.4(t.2H) 1.1˜2.0(m.12H) 0.9(t.3H)      64 (CH.sub.2).sub.9      CH.sub.3     ##STR42##      1.477 7.8˜8.2(m.2H) 7.2˜7.7(m.3H) 4.7˜5.4(m.2H)     2.2(t.2H)1.0˜1.9(m.22H) 0.9(t.3H)  65      "     ##STR43##      1.481 7.75(d.2H) 7.05(d.2H) 4.7˜5.3(m.2H) 2.4(s.3H)2.2(t.2H)     1.1˜2.0(m.22H) 0.9(t.3H)  66      "     ##STR44##      1.488  7.9(d.2H) 6.8(d.2H) 4.8˜5.4(m.2H) 3.8(s.3H) 2.2(t.2H)     1.1˜2.0(m.22H) 0.9(t.3H)  67      "     ##STR45##      1.488  7.85(d.2H) 7.3(d.2H) 4.7˜5.3(m.2H) 2.2(t.2H) 1.1˜2.0(     m.22H) 0.9(t.3H)  68      "     ##STR46##      1.491  7.15(s.2H) 4.8˜5.4(m.2H) 3.8(d.9H) 2.2(t.2H)1.1˜2.0(m     .22H) 0.9(t.3H)  69      "     ##STR47##      1.475  7.2(m.5H) 4.6˜5.1(m.2H) 3.5(s.2H) 2.1(t.2H)1.0˜1.9(m.     22H) 0.9(t.3H)  70      "     ##STR48##      1.475  7.15(s.5H) 4.7˜5.2(m.2H) 2.8(t.2H) 2.7(t.2H)2.2(t.2H)     1.0˜1.9(m.22H) 0.9(t.3H)  71      "     ##STR49##      1.478  6.7˜7.4(m.5H) 4.7˜5.2(m.2H) 4.5(s.2H) 2.2(t.2H)1.0.ab     out.1.9(m.22H) 0.9(t.3H)  72      "     ##STR50##      1.474 7.2(s.5H) 4.6˜5.1(m.2H) 3.3(t.1H) 0.6˜2.3(m.28H)  73     (CH.sub.2).sub.4      CH.sub.3     ##STR51##      1.536  7.65(s.1H) 6.8˜7.4(m.10H) 4.7˜5.3(m.2H) 2.0˜2.5     (t.2H)1.1˜2.0(m.12H) 0.9(t.3H)  74 (CH.sub.2).sub.9 CH.sub.3    "     1.525  7.6(s.1H) 6.7˜7.4(m.10H) 4.7˜5.1(m.2H) 2.0˜2.4(t     .2H)      1.1˜2.0(m.22H) 0.9(t.3H)  75 (CH.sub.2).sub.4 CH.sub.4      ##STR52##      1.496  7.1˜7.8(m.5H) 6.8(d.1H) 4.7˜5.3(m.2H) 2.3(t.2H)1.1.ab     out.2.0(m.12H) 0.9(t.3H)  76      "     ##STR53##      1.506  7.30(m.5H) 6.15(m.1H) 4.8˜5.3(m.2H) 2.56(m.3H)2.30(t.2H)     1.1˜1.9(m.12H) 0.86(t.3H)  77 (CH.sub.2).sub.9      CH.sub.3     ##STR54##      1.495  7.32(m.5H) 6.10(m.1H) 4.8˜5.3(m.2H) 2.58(m.3H)2.30(t.2H)     1.0˜1.9(m.22H) 0.89(t.3H)  78 (CH.sub.2).sub.4      CH.sub.3     ##STR55##      1.539 7.21(s.10H) 6.30(s.1H) 4.5˜5.2(m.2H) 2.28(t.2H)1.2˜1.9     (m.6H) 1.08(d.6H) 0.89(t.3H)  79 (CH.sub.2).sub.9      CH.sub.3     ##STR56##      1.520  7.22(s.10H) 6.30(s.1H) 4.6˜5.2(m.2H) 2.30(t.2H)1.2˜1.     9(m.16H) 1.10(d.6H) 0.9(t.3H) 80 (CH.sub.2).sub.6      CH.sub.3     ##STR57##      1.525  7.7(s.1H) 6.8˜7.5(m.10H) 4.7˜5.3(m.2H) 2.25(t.2H)1.0.     about.2.0(m.18H) 0.9(t.3H)  81      "     ##STR58##      1.498 7.0˜7.5(m.5H) 6.0(m.1H) 4.6˜5.2(m.2H) 2.5(m.3H)2.2(t.2     H) 1.0˜2.0(m.18H) 0.9(t.3H)

The butanediol diester (I) is described below with respect to itsantiulcer action and acute toxicity.

(i) Antiulcer action

Wister male rats each weighing about 200 g were given, after fasting for24 hours, orally 25 mg/kg of indomethacin suspended in 1% aq. solutionof sodium carboxymethylcellulose. Five hours later, 1 ml ofphysiological saline containing 2% brilliant blue was injectedintravenously on their tails, and 10 minutes later, they wereslaughtered and their stomachs were removed. After fixation by injecting12 ml of 1% formalin aq. solution, the stomachs were extended on a flatplate and the injured parts on the stomach was measured with slidecalipers. The sum of the lengths in mm was regarded as the ulcer index.

The test compound was emulsified or suspended in physiological salinecontaining one drop of polysolvate 80, and this was given orally orsubcutaneously on the back one hour before administration ofindomethacin.

The ulcer inhibition ratio was obtained from the following formula.

Inhibition ratio (%)=A/B×100

A: (ulcer index of control group)--(ulcer index of test group given thetest compound)

B: (ulcer index of control group)

The results are shown in Table 2, in which the compound numberscorrespond to those in Table 1.

                  TABLE 2                                                         ______________________________________                                        Compd.    No. of  Dosage           Inhibition                                 No.       rats    (mg/kg)    Route ratio (%)                                  ______________________________________                                        1         5       200        Subcu-                                                                              92                                                                      tane-                                                                         ously                                            2         "       "          Subcu-                                                                              90                                                                      tane-                                                                         ously                                            3         "       "          Subcu-                                                                              50                                                                      tane-                                                                         ously                                            4         "       "          Subcu-                                                                              74                                                                      tane-                                                                         ously                                            6         "       "          Subcu-                                                                              57                                                                      tane-                                                                         ously                                            7         "       "          Subcu-                                                                              30                                                                      tane-                                                                         ously                                            15        "       "          Subcu-                                                                              47                                                                      tane-                                                                         ously                                            16        "       "          Subcu-                                                                              86                                                                      tane-                                                                         ously                                            17        "       "          Subcu-                                                                              37                                                                      tane-                                                                         ously                                            22        "       "          Subcu-                                                                              91                                                                      tane-                                                                         ously                                            24        "       "          Subcu-                                                                              90                                                                      tane-                                                                         ously                                            25        "       "          Subcu-                                                                              95                                                                      tane-                                                                         ously                                            28        "       "          Subcu-                                                                              62                                                                      tane-                                                                         ously                                            31        "       "          Subcu-                                                                              91                                                                      tane-                                                                         ously                                            34        "       "          Subcu-                                                                              75                                                                      tane-                                                                         ously                                            35        "       "          Subcu-                                                                              77                                                                      tane-                                                                         ously                                            37        "       "          Subcu-                                                                              85                                                                      tane-                                                                         ously                                            40        "       "          Subcu-                                                                              99                                                                      tane-                                                                         ously                                            45        "       "          Subcu-                                                                              84                                                                      tane-                                                                         ously                                            46        "       "          Subcu-                                                                              56                                                                      tane-                                                                         ously                                            48        4       "          Orally                                                                              84                                         48        5       300        Subcu-                                                                              96                                                                      tane-                                                                         ously                                            54        "       200        Subcu-                                                                              87                                                                      tane-                                                                         ously                                            57        "       "          Subcu-                                                                              80                                                                      tane-                                                                         ously                                            60        "       "          Subcu-                                                                              41.4                                                                    tane-                                                                         ously                                            62        "       "          Subcu-                                                                              50.0                                                                    tane-                                                                         ously                                            64        "       "          Subcu-                                                                              41.3                                                                    tane-                                                                         ously                                            68        "       "          Subcu-                                                                              89.3                                                                    tane-                                                                         ously                                            70        "       "          Subcu-                                                                              45.9                                                                    tane-                                                                         ously                                            71        "       "          Subcu-                                                                              59.2                                                                    tane-                                                                         ously                                            ______________________________________                                    

As Table 2 indicates, all of the test compounds are apparently effectivein antiulcer action.

(ii) Acute toxicity

ddy male mice, arranged in groups each consisting of five mice, weregiven intraperitoneally 1000 mg/kg of the test compounds Nos. 1-4, 8-10,14-18, 21, 22, 24, 25, 28, 31, 34, 35, 37, 45, 46, 48, 54, 57, 60, 62,64, 68, 70, and 71 (as shown in Table 1) dissolved in cotton seed oil.After observation for seven days, all the mice lived without anyanomaly. The test compounds were found to have an LD₅₀ higher than 1000mg/kg and a very low toxicity.

The antiulcer drug of this invention can be administered either orallyor non-orally in the form of powder, tablets, capsules, granules,solutions, injections (subcutaneous, intramuscular, intravenous),transfusion, and suppositories.

The above-mentioned preparations can be manufactured by the knownmethods. Powder, tablets, capsules, and granules can be preparedcombining butanediol diester with a diluting agent such as starch,lactose, and mannitol; a binder such as sodium carboxymethylcelluloseand hydroxypropylcellulose; a disintegrator such as crystallinecellulose calcium carboxymethylcellulose; a lubricant such as talc andmagnesium stearate; and a fluidity improving agent such as light silicicanhydride. Solutions and injections can be prepared by dissolvingbutanediol diester in olive oil or peanut oil, or by dissolving orsuspending butanediol diester in water or physiological saline using ananionic surface active agent such as polysolvate 60 and polysolvate 80.Suppositories can be prepared by dispersing butanediol diester in cacaobutter or synthetic fats in the conventional manner.

The antiulcer drug thus prepared is administered at the dosage of 0.1 to1000 mg/kg (orally) and 0.05 to 500 mg/kg (non-orally) once to severaltimes a day for adults.

The invention is illustrated by the following examples.

EXAMPLE 1 Synthesis of Compound No. 22

(1) Dissolve 9 g (0.1 mole) of 2,3-butanediol in 50 ml of ether.

(2) Add 10 ml of pyridine.

(3) With stirring and ice cooling, add dropwise 30 ml of ether solutioncontaining 16.65 g (0.1 mole) of cinnamoyl chloride.

(4) Continue stirring at the cooled temperature for 30 minutes andfurther continue stirring at room temperature for 4 hours.

(5) Add water and separate the ether layer.

(6) Wash the ether layer with water, 10% hydrochloric acid, water,saturated sodium hydrogenbicarbonate solution, and water in the orderlisted.

(7) Dry the solution with anhydrous sodium sulfate.

(8) Remove ether by distillation under reduced pressure.

(9) Purify the residue by column chromatography (SiO₂) to give 9.4 g ofcolorless liquid monoester (yield 42.7%).

(10) Dissolve 9.4 g (0.043 mole) of this monoester in 120 ml of ether.

(11) Add 6.8 ml of pyridine.

(12) With stirring and ice cooling, add dropwise 120 ml of ethersolution containing 5.75 g (0.043 mole) of caproyl chloride.

(13) Continue stirring at the cooled temperature for 30 minutes andfurther continue stirring at room temperature for 4 hours.

(14) Add water and separate the ether layer.

(15) Wash the ether layer with water, 10% hydrochloric acid, water,saturated sodium hydrogenbicarbonate solution, and water in the orderlisted.

(16) Dry the solution with anhydrous sodium sulfate.

(17) Remove ether by distillation under reduced pressure.

(18) Purify the residue by column chromatography (SiO₂) to give 9.3 g ofcolorless liquid which is identified as compound No. 22 in Table 1(yield 71%).

n_(D) ²⁰ 1.514, IR ν_(max) ^(neat) cm⁻¹ 1720 (C═O).

EXAMPLE 2 Synthesis of Compound No. 35

(1) With stirring and ice cooling, add dropwise 40 ml of ether solutioncontaining 9 g (0.1 mole) of 2,3-butanediol to 40 ml of ether in which 4g (0.1 mole) of sodium hydride, is suspended.

(2) Continue stirring at the cooled temperature for 30 minutes andfurther continue stirring at room temperature for 30 minutes.

(3) With ice cooling again, add dropwise 40 ml of ether solutioncontaining 20.45 g (0.1 mole) of undecanoyl chloride.

(4) Stir at room temperature for 3 hours.

(5) Add water and separate the ether layer.

(6) Carry out the same steps as in Example 1 to give 10.5 g of colorlessliquid monoester (yield 40.7%).

(7) Dissolve 10.32 g (0.04 mole) of this monoester in 80 ml oftetrahydrofuran.

(8) Add 6.4 ml of pyridine.

(9) With stirring and ice cooling, add dropwise 80 ml of tetrahydrofuransolution containing 7.86 g (0.04 mole) of p-methoxycinnamoyl chloride.

(10) Continue stirring at the cooled temperature for 30 minutes andfurther continue stirring at room temperature for 4 hours.

(11) Remove the solvent by distillation under reduced pressure.

(12) Dissolve the residue in chloroform.

(13) Wash the chloroform solution with water, 10% hydrochloric acid,water, saturated sodium hydrogenbicarbonate solution, and water in theorder listed.

(14) Dry the solution with anhydrous sodium sulfate.

(15) Remove chloroform by distillation under reduced pressure.

(16) Purify the residue by column chromatography (SiO₂) to give 6 g ofcolorless liquid which is identified as compound No. 35 in Table 1(yield 35.8%).

n_(D) ²⁰ 1.519, IR ν_(max) ^(neat) cm⁻¹ 1720 (C═O).

EXAMPLE 3 Synthesis of Compound No. 43

(1) Dissolve 4.5 g (0.05 mole) of 2,3-butanediol in 60 ml oftetrahydrofuran.

(2) Add 10 ml of pyridine.

(3) With stirring and ice cooling, add dropwise 60 ml of tetrahydrofuransolution containing 19.15 g (0.1 mole) of α-cyanocinnamoyl chloride.

(4) Continue stirring at the cooled temperature for 30 minutes andfurther continue stirring at room temperature for 4 hours.

(5) Remove the solvent by distillation under reduced pressure.

(6) Dissolve the residue in chloroform.

(7) Wash the chloroform solution with water, 10% hydrochloric acid,water, saturated sodium hydrogenbicarbonate solution, and water in theorder listed.

(8) Dry the solution with anhydrous sodium sulfate.

(9) Remove chloroform by distillation under reduced pressure.

(10) Recrystallize the residue from benzene to give 12.4 g of lightyellow needle crystal, which is identified as compound No. 43 in Table 1(yield 62%).

Melting point: 177° to 180° C.

IR ν_(max) ^(KBr) cm⁻¹ 1720 (C═O).

EXAMPLE 4 Synthesis of Compound 60

(1) With stirring and ice cooling, add 40 ml of ether solutioncontaining 6.3 g (0.07 mole) of 2,3-butanediol to 40 ml of ether inwhich 3.0 g (0.075 mole) of sodium hydride is suspended.

(2) Continue stirring at the cooled temperature for 30 minutes andfurther continue stirring at room temperature for 30 minutes.

(3) With ice cooling again, add dropwise 40 ml of ether solutioncontaining 11.9 g (0.07 mole) of p-anisoyl chloride.

(4) Stir at room temperature for 3 hours.

(5) Add water and separate the ether layer.

(6) Wash the ether layer with water, 10% hydrochloric acid, water,saturated sodium hydrogencarbonate solution, and water in the orderlisted.

(7) Dry the ether layer with anhydrous sodium sulfate.

(8) Remove ether by distillation under reduced pressure.

(9) Purify the residue by column chromatography (SiO₂) to give 6.8 g ofcolorless liquid monoester (yield 43.4%).

(10) Dissolve 2.02 g (0.009 mole) of this monoester in 20 ml of ether.

(11) Add 2 ml of pyridine.

(12) With stirring and ice cooling, add dropwise 20 ml of ether solutioncontaining 1.22 g (0.009 mole) of n-caproyl chloride.

(13) Continue stirring at the cooled temperature for 30 minutes andfurther continue stirring at room temperature for 3 hours.

(14) Add water and separate the ether layer.

(15) Wash the ether layer with water, 10% hydrochloric acid, water,saturated sodium hydrogenbicarbonate solution, and water in the orderlisted.

(16) Dry the solution with anhydrous sodium sulfate.

(17) Remove ether by distillation under reduced pressure.

(18) Purify the residue by column chromatography (SiO₂) to give 2.7 g ofcolorless liquid which is identified as compound No. 60 in Table 1(yield 93.2%).

n_(D) ²⁰ 1.492, IR ν_(max) ^(neat) cm⁻¹ 1720 C═O).

EXAMPLE 5 Synthesis of Compound 68

(1) With stirring and ice cooling, and 20 ml of ether solutioncontaining 2.7 g (0.03 mole) of 2,3-butanediol to 40 ml oftetrahydrofuran in which 1.2 g (0.03 mole) of sodium hydride issuspended.

(2) Continue stirring at the cooled temperature for 30 minutes andfurther continue stirring at room temperature for 30 minutes.

(3) With ice cooling again, add dropwise 40 ml of tetrahydrofuransolution containing 6.92 g (0.03 mole) of 3,4,5-trimethoxybenzoylchloride.

(4) Stir at room temperature for 5 hours.

(5) Remove the solvent by distillation under reduced pressure.

(6) Dissolve the residue in chloroform.

(7) Wash the chloroform layer with water, 10% hydrochloric acid, water,saturated sodium hydrogenbicarbonate solution, and water in the orderlisted.

(8) Dry the chloroform layer with anhydrous sodium sulfate.

(9) Remove chloroform by distillation under reduced pressure.

(10) Purify the residue by column chromatography (SiO₂) to give 3.66 gof colorless liquid monoester (yield 43%).

(11) Dissolve 2.84 g (0.01 mole) of this monoester in 20 ml of ether.

(12) Add 2 ml of pyridine.

(13) With ice cooling, add dropwise 20 ml of ether solution containing2.05 g (0.01 mole) of undecanoyl chloride.

(14) Continue stirring at the cooled temperature for 30 minutes andfurther continue stirring at room temperature for 3 hours.

(15) Add water and separate the ether layer.

(16) Wash the ether layer with water, 10% hydrochloric acid, water,saturated sodium hydrogenbicarbonate solution, and water in the orderlisted.

(17) Dry the ether layer with anhydrous sodium sulfate.

(18) Remove ether by distillation under reduced pressure.

(19) Purify the residue by column chromatography (SiO₂) to give 2.04 gof colorless liquid which is identified as compound No. 68 in Table 1(yield 50%).

n_(D) ²⁰ 1.491, IR ν_(max) ^(neat) cm⁻¹ 1720 (C═O).

EXAMPLE 6 Synthesis of Compound No. 70

(1) Dissolve 9 g (0.1 mole) of 2,3-butanediol in 50 ml of ether.

(2) Add 10 ml of pyridine.

(3) With stirring and ice cooling, add dropwise 75 ml of ether solutioncontaining 20.5 g (0.1 mole) of undecanoyl chloride.

(4) Continue stirring at the cooled temperature for 30 minutes andfurther continue stirring at room temperature for 4 hours.

(5) Add water and separate the ether layer.

(6) Carry out the treatment as in Example 4 to give 13.2 g of colorlessliquid monoester (yield 51%).

(7) Dissolve 12.9 g (0.05 mole) of this monoester in 100 ml of ether.

(8) Add 10 ml of pyridine.

(9) With stirring and ice cooling, add dropwise 100 ml of ether solutioncontaining 8.43 g (0.05 mole) of phenylpropionyl chloride.

(10) Continue stirring at the cooled temperature for 30 minutes andfurther continue stirring at room temperature for 3 hours.

(11) Add water and separate the ether layer.

(12) Wash the ether layer with water, 10% hydrochloric acid, water,saturated sodium hydrogenbicarbonate solution, and water in the orderlisted.

(13) Dry the solution with anhydrous sodium sulfate.

(14) Remove ether by distillation under reduced pressure.

(15) Purify the residue by column chromatography (SiO₂) to give 16.2 gof colorless liquid which is identified as compound No. 70 in Table 1(yield 85.3%).

n_(D) ²⁰ 1.475, IR ν_(max) ^(neat) cm⁻¹ 1720 (C═O).

EXAMPLE 7 Preparation of Tablet

A tablet of the following composition was prepared according to theconventional manner.

    ______________________________________                                        Butanediol diester  100       mg                                              (Compound No. 1 in Table 1)                                                   Light silicic anhydride                                                                           100       mg                                              Crystalline cellulose                                                                             50        mg                                              Hydroxypropyl cellulose                                                                           10        mg                                              Calcium carboxymethylcellulose                                                                    25        mg                                              Talc                4         mg                                              Magnesium stearate  2         mg                                              Lactose             An amount sufficient                                                          to bring the final                                                            weight to 350 mg                                          ______________________________________                                    

EXAMPLE 8 Preparation of Granules

Granules of the following composition were prepared according to theconventional manner.

    ______________________________________                                        Butanediol diester      100    mg                                             (Compound No. 1 in Table 1)                                                   Light silicic anhydride 100    mg                                             Mannitol                650    mg                                             Starch                  135    mg                                             Polyvinyl pyrrolidone   15     mg                                             Total                   1000   mg                                             ______________________________________                                    

EXAMPLE 9 Preparation of Injection

An oil injection of the following composition were prepared according tothe conventional manner.

    ______________________________________                                        Butanediol diester      100    mg                                             (Compound No. 2 in Table 1)                                                   Peanut oil              1900   mg                                             Total                   2000   mg                                             ______________________________________                                    

EXAMPLE 10 Preparation of Suppository

A suppository of the following composition were prepared according tothe conventional manner.

    ______________________________________                                        Butanediol diester      100    mg                                             (Compound No. 2 in Table 1)                                                   Cacao butter            1000   mg                                             Total                   1100   mg                                             ______________________________________                                    

EXAMPLE 11 Preparation of Tablet

A tablet of the following composition was prepared according to theconventional manner.

    ______________________________________                                        Butanediol diester  100        mg                                             (Compound No. 31 in Table 1)                                                  Light silicic anhydride                                                                           100        mg                                             Crystalline cellulose                                                                             50         mg                                             Hydroxypropyl cellulose                                                                           10         mg                                             Calcium carboxymethylcellulose                                                                    25         mg                                             Talc                4          mg                                             Magnesium stearate  2          mg                                             Lactose             An amount sufficient                                                          to bring the final                                                            weight to 350 mg                                          ______________________________________                                    

EXAMPLE 12 Preparation of Granules

Granules of the following composition were prepared according to theconventional manner.

    ______________________________________                                        Butanediol diester      100    mg                                             (Compound No. 25 in Table 1)                                                  Light silicic anhydride 100    mg                                             Mannitol                650    mg                                             Starch                  135    mg                                             Polyvinyl pyrrolidone   15     mg                                             Total                   1000   mg                                             ______________________________________                                    

EXAMPLE 13 Preparation of Injection

An oil injection of the following composition were prepared according tothe conventional manner.

    ______________________________________                                        Butanediol diester      100    mg                                             (Compound No. 31 in Table 1)                                                  Peanut oil              1900   mg                                             Total                   2000   mg                                             ______________________________________                                    

EXAMPLE 14 Preparation of Suppository

A suppository of the following composition were prepared according tothe conventional manner.

    ______________________________________                                        Butanediol diester      100    mg                                             (Compound No. 40 in Table 1)                                                  Cacao butter            1000   mg                                             Total                   1100   mg                                             ______________________________________                                    

EXAMPLE 15 Preparation of Tablet

A tablet of the following composition was prepared according to theconventional manner.

    ______________________________________                                        Butanediol diester  100        mg                                             (Compound No. 68 in Table 1)                                                  Light silicic anhydride                                                                           100        mg                                             Crystalline cellulose                                                                             50         mg                                             Hydroxypropyl cellulose                                                                           10         mg                                             Calcium carboxymethylcellulose                                                                    25         mg                                             Talc                4          mg                                             Magnesium stearate  2          mg                                             Lactose             An amount sufficient                                                          to bring the final                                                            weight to 350 mg                                          ______________________________________                                    

EXAMPLE 16 Preparation of Granules

Granules of the following composition were prepared according to theconventional manner.

    ______________________________________                                        Butanediol diester      100    mg                                             (Compound No. 62 in Table 1)                                                  Light silicic anhydride 100    mg                                             Mannitol                650    mg                                             Starch                  135    mg                                             Polyvinyl pyrrolidone   15     mg                                             Total                   1000   mg                                             ______________________________________                                    

EXAMPLE 17 Preparation of Injection

An oil injection of the following composition were prepared according tothe conventional manner.

    ______________________________________                                        Butanediol diester      100    mg                                             (Compound No. 71 in Table 1)                                                  Peanut oil              1900   mg                                             Total                   2000   mg                                             ______________________________________                                    

EXAMPLE 18 Preparation of Suppository

A suppository of the following composition were prepared according tothe conventional manner.

    ______________________________________                                        Butanediol diester      100    mg                                             (Compound No. 68 in Table 1)                                                  Cacao butter            1000   mg                                             Total                   1100   mg                                             ______________________________________                                    

What is claimed is:
 1. An antiulcer composition comprising, as an activeingredient, an antiulcer effective amount of a 2,3-butanediol diesterrepresented by the formula (I): ##STR59## where R_(A) is a saturatedalkyl group which may have a branched chain, or a group represented bythe formula ##STR60## where R₁ is hydrogen, cyano or lower alkyl, andR₂is hydrogen, halogen, lower alkyl, lower alkyloxy or lower acyloxy;R_(B) is a saturated alkyl group which may have a branched chain, phenylgroup which may be substituted with lower alkyl, lower alkoxy orhalogen, phenyl alkyl, phenyl propenyl, phenyloxy alkyl or a grouprepresented by the formula ##STR61## where R₃ is hydrogen, halogen,cyano, lower alkyl or phenyl, R₄ is hydrogen, lower alkyl or phenyl, andR₅ is phenyl which may be substituted with lower alkyl, lower alkoxy,acyloxy or halogen; and a pharmaceutically acceptable compound selectedfrom the group consisting of a diluent, a binder, a disintegrator, alubricant, a fluidity improving agent, olive oil, peanut oil, water,physiological saline, cacao butter and synthetic fat.
 2. The antiulcercomposition according to claim 1, wherein the diluent is starch, lactoseor mannitol.
 3. The antiulcer composition according to claim 1, whereinthe binder is sodium carboxymethylcellulose or hydroxypropylcellulose.4. The antiulcer composition according to claim 1, wherein thedisintegrator is crystalline cellulose calcium carboxymethylcellulose.5. The antiulcer composition according to claim 1, wherein the lubricantis talc or magnesium stearate.
 6. The antiulcer composition according toclaim 1, wherein the fluidity improving agent is light silicicanhydride.
 7. The antiulcer composition according to claim 1, in theform of powder, tablets, capsules, granules, solutions or suppositories.8. The antiulcer composition according to claim 1 in a form for oraladministration.